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Friday, February 10, 2012

Is this a potential cure for Alzheimer's?

Today in my RSS feed I saw this paper in Science. The article, ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models" by Cramer et. al comes from the lab of Gary Landreth at Case Western University.

In this article, the authors applied an FDA approved retinoid-X-receptor (RXR) agonist, Bexarotene, to a mouse model of Alzheimer's disease (AD). Their rationale was that the RXR agonist would up-regulate levels of ApoE. ApoE is a lipoprotein that, along with Aβ, has been implicated in the pathogenesis of AD. It is known that ApoE promotes the proteolysis of Aβ. Also, RXR agonists activate microglial cells so that they remove insoluble Aβ plaques.

Knowing that ApoE is under the transcription control of RXR, the authors reasoned that using Bexarotene in mice with an AD phenotype would active RXR, upregulate ApoE, and thereby promote the proteolytic clearance of Aβ. And that is precisely what happened. After one dose Bexarotene, the amount of soluble Aβ in the brain interstitial fluid had reduced by 25%. This effect was only seen in mice that had ApoE. An ApoE-null mice strain was used as a control. No Aβ clearance was seen in this strain, supporting the hypothesis that ApoE is responsible for the clearance of Aβ.

When they administered Bexarotene for 3, 7 and 14 days, the authors saw a time-dependent decline Aβ. Impressively, by day 14, they measured a 30% reduction in soluble Aβ and a 75% reduction in total Aβ plaques.

That's all well and good, but how did this reduction in Aβ affect the functioning of these mice with AD?

Cognition and memory were rapidly restored in the mice after getting Bexarotene. Olfactory impairment, which is characteristic feature of AD and is associated with Aβ burden, improved after 9 days of Bexarotene treatment.

The implications of this study for medicine could be huge. It remains to be seen if the impressive results in mice will hold true in humans as well. I don't think there is much reason to doubt that there won't be a similar benefit in people. Clinical trials using Bexarotene are under way to be sure. That Bexarotene is already FDA approved, albeit for a different indication, is a tremendous advantage. Re-purposing a drug is easy. Taking a compound from beaker to bedside is much more difficult, time consuming and costly. Patients with Alzheimer's could benefit sooner than later if clinical trials hold out. I'll have my eye on future developments of this work.

1 comment:

I personally believe that bexarotene is a potential cure for AD. It is good to know that the drug that is already in the market has a potential to cure other diseases. However, unless the studies declare that successful in human, then the issues accompanied by this drug will be ended.